NO174412B - Procedure for Preparing a Pharmaceutical Formulation with Programmed Release for Oral Use - Google Patents
Procedure for Preparing a Pharmaceutical Formulation with Programmed Release for Oral Use Download PDFInfo
- Publication number
- NO174412B NO174412B NO873072A NO873072A NO174412B NO 174412 B NO174412 B NO 174412B NO 873072 A NO873072 A NO 873072A NO 873072 A NO873072 A NO 873072A NO 174412 B NO174412 B NO 174412B
- Authority
- NO
- Norway
- Prior art keywords
- granules
- naproxen
- release
- pharmaceutical formulation
- programmed release
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 239000008187 granular material Substances 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 27
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 19
- 229960002009 naproxen Drugs 0.000 claims description 19
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 238000013270 controlled release Methods 0.000 claims description 5
- 239000003826 tablet Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 238000012216 screening Methods 0.000 claims description 4
- 229920002261 Corn starch Polymers 0.000 claims description 3
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- 239000008120 corn starch Substances 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000000314 lubricant Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000007908 dry granulation Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- 239000013020 final formulation Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000005550 wet granulation Methods 0.000 claims description 2
- 238000009472 formulation Methods 0.000 description 10
- 230000001105 regulatory effect Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000001741 anti-phlogistic effect Effects 0.000 description 2
- 230000036765 blood level Effects 0.000 description 2
- 229920003086 cellulose ether Polymers 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000003340 retarding agent Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229960004187 indoprofen Drugs 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av en farmasøytisk formulering med programmert frigjøring for oral anvendelse, inneholdende naproxen som aktivt prinsipp. The present invention relates to a method for producing a pharmaceutical formulation with programmed release for oral use, containing naproxen as active principle.
En fagmann på området kjenner godt til de problemer som er forbundet med gjentatt administrering av legemidler. Bort-sett fra de ubehageligheter og den besværlighet, hovedsakelig psykologisk, som pasienten kan oppleve når han må huske på å ta den bestemte medisin tre eller fire ganger pr. dag (som for eksempel hender når det gjelder paracetamol), må man ta hensyn til at ut fra et absorpsjonskinetikk-synspunkt gir gjentatt administrering meget høye blodnivåer av det legemiddel som gjentatte ganger opptrer i pasientens organisme, med en betydelig økning i muligheten for bivirkninger. I littera-turen er det beskrevet mange metodikker, vanligvis kalt "retardering", ved hjelp av hvilke antallet av administrer-inger av et legemiddel kan reduseres mens dets terapeputiske effektivitet holdes uforandret hele tiden. A person skilled in the art is well aware of the problems associated with repeated administration of drugs. Apart from the unpleasantness and the difficulty, mainly psychological, that the patient may experience when he has to remember to take the particular medicine three or four times a day. day (as happens, for example, in the case of paracetamol), one must take into account that, from an absorption kinetics point of view, repeated administration produces very high blood levels of the drug which repeatedly appears in the patient's organism, with a significant increase in the possibility of side effects. In the literature, many methodologies are described, usually called "retardation", by means of which the number of administrations of a drug can be reduced while its therapeutic effectiveness is kept unchanged at all times.
Således er for eksempel indometacintabletter med langsom frigjøring, hvor det aktive prinsipp er belagt med en film eller en hydrofil polymer og med en celluloseeter, patentsøkt i japansk utlagt patentsøknad J 58170712, mens diklofenac, som er et annet velkjent antiflogistikum, i japansk utlagt patent-søknad J 59084821 er blandet med /3-cyklodextrin. I tysk utlagt patentsøknad DE 3001797 mikroinnkapsles indoprofen, et godt smertestillende og anti-inflammatorisk middel som har den ulempe at det har kort plasma-halveringstid, i et beskyttende lag av en celluloseeter, idet man således får en betydelig forbedring av dens plasma-halveringstid. Endelig er det i europeiske patenter EP 0094116, EP 0094117 og EP 0094123 beskrevet granuler som har et dobbelt belegg; det første er laget av polyvinylpyrrolidon og det annet av akrylpolymerer eller av celluloseestere eller av fett- eller oljesubstanser, hvilket skulle muliggjøre en bedre frigjøring av antiflogis-tika både i magesekken og i tarmen. Thus, for example, indomethacin tablets with slow release, where the active principle is coated with a film or a hydrophilic polymer and with a cellulose ether, are patent pending in Japanese patent application J 58170712, while diclofenac, which is another well-known antiphlogistic, in Japanese patent application application J 59084821 is mixed with /3-cyclodextrin. In published German patent application DE 3001797, indoprofen, a good analgesic and anti-inflammatory agent which has the disadvantage of having a short plasma half-life, is microencapsulated in a protective layer of a cellulose ether, thereby obtaining a significant improvement in its plasma half-life. Finally, European patents EP 0094116, EP 0094117 and EP 0094123 describe granules having a double coating; the first is made of polyvinylpyrrolidone and the second of acrylic polymers or of cellulose esters or of fatty or oily substances, which should enable a better release of antiphlogistics both in the stomach and in the intestine.
Når det gjelder alle disse galeniske formuleringer, er imidlertid begynnelses-frigjøringen av den aktive bestanddel gradvis og langsom, slik at den terapeutiske virkning begynner først noen timer etter administrering. Dette er en klar ulempe, særlig når det gjelder legemidler som samtidig har anti-inflammatorisk, smertestillende og feberstillende aktivitet, hvor det ofte trengs hurtig frigjøring for oppnåelse av en omgående smertestillende virkning, ved siden av langsom og regelmessig frigjøring for å helbrede inflammasj onen. In the case of all these galenic formulations, however, the initial release of the active ingredient is gradual and slow, so that the therapeutic effect begins only a few hours after administration. This is a clear disadvantage, especially when it comes to drugs that simultaneously have anti-inflammatory, pain-relieving and antipyretic activity, where rapid release is often needed to achieve an immediate pain-relieving effect, alongside slow and regular release to heal the inflammation.
Formålet med den foreliggende oppfinnelse er fremstilling av nye galeniske formuleringer med programmert frigjøring, omgående og forsinket. Disse formuleringer kan administreres oralt. For å unngå ulempene ved de kjente formuleringer med regulert frigjøring, og for oppnåelse av en tilstrekkelig terapeutisk respons fra begynnelsen, fremstilles de galeniske formuleringer ved fremgangsmåten ifølge den foreliggende oppfinnelse gjennom de følgende trinn: a) fremstilling av et granulat med momentan frigjøring ved tørrgranulering av naproxen sammen med bindemidler valgt fra polyvinylpyrrolidon og laktose med sprengningsmidler valgt fra mais-stivelse og natriumstivelsesglykolat, og med magnesiumstearat som smøremiddel, og deretter siling av granulatet på en sikt med maskevidde på 1 mm; b) fremstilling av et granulat med kontrollert frigjøring ved våtgranulering av naproxen sammen med retarderingsmidler valgt fra etylcellulose, hydrogenert ricinusolje og blandinger derav, ved hjelp av 95% etylalkohol, deretter tørking av granulatet i ovn ved 50°C, og siling av det gjennom en sikt med masker på 1 mm; c) fremstilling av den farmasøytiske formulering med programmert frigjøring, ved å blande de to granulater fremstilt ifølge trinn a) og b) i slike vektforhold at mengden av naproxen i sluttformuleringen tilhører hvert av de to granulater i en prosentsammensetning mellom 3 0% og 7 0%, og deretter fremstiller tabletter, kapsler og granulater for suspensjon eller for oppløsning i egnede flytende medier av den resul-terende blanding ved kjente teknikker. The purpose of the present invention is the production of new galenic formulations with programmed release, immediate and delayed. These formulations can be administered orally. In order to avoid the disadvantages of the known formulations with controlled release, and to achieve a sufficient therapeutic response from the beginning, the galenic formulations are prepared by the method according to the present invention through the following steps: a) preparation of a granule with instantaneous release by dry granulation of naproxen together with binders selected from polyvinylpyrrolidone and lactose with disintegrants selected from corn starch and sodium starch glycolate, and with magnesium stearate as a lubricant, and then screening the granules on a 1 mm mesh screen; b) producing a controlled release granule by wet granulation of naproxen together with retarders selected from ethyl cellulose, hydrogenated castor oil and mixtures thereof, using 95% ethyl alcohol, then drying the granulate in an oven at 50°C, and screening it through a sieve with meshes of 1 mm; c) preparation of the pharmaceutical formulation with programmed release, by mixing the two granules prepared according to steps a) and b) in such a weight ratio that the amount of naproxen in the final formulation belongs to each of the two granules in a percentage composition between 30% and 70 %, and then prepare tablets, capsules and granules for suspension or for dissolution in suitable liquid media from the resulting mixture by known techniques.
Granulatet med umiddelbar frigjøring inneholder for-trinnsvis fra 60 til 70 % aktivt prinsipp, fra 20 til 30 % bindemidler, fra 8 til 12 % sprengningsmidler og fra 0,2 til 1% av et smøremiddel. The immediate-release granules preferably contain from 60 to 70% active principle, from 20 to 30% binders, from 8 to 12% explosives and from 0.2 to 1% of a lubricant.
Granulatet med regulert frigjøring inneholder fortrinns-vis 60 til 70 % aktivt prinsipp og fra 30 til 40 % av et retarderingsmiddel eller av en blanding av retarderingsmidler. The granules with regulated release preferably contain 60 to 70% active principle and from 30 to 40% of a retarding agent or of a mixture of retarding agents.
Ved et foretrukket, men ikke begrensende, aspekt av oppfinnelsen fremstilles granulatene med en sammensetning som følger: a) Granulat med umiddelbar frigiøring 60-70% naproksen, 17-23% laktose, 3-7% polyvinylpyrrolidon, 4-8% maisstivelse, 3-6% natriumstivelsesglykolat, 0,2-0,5% magnesiumstearat. In a preferred, but not limiting, aspect of the invention, the granules are produced with a composition as follows: a) Granules with immediate release 60-70% naproxen, 17-23% lactose, 3-7% polyvinylpyrrolidone, 4-8% corn starch, 3 -6% sodium starch glycolate, 0.2-0.5% magnesium stearate.
b) Granulat med regulert frigjøring b) Granules with regulated release
60-70% naproksen, 20-30% hydrogenert ricinusolje, 6-12% 60-70% naproxen, 20-30% hydrogenated castor oil, 6-12%
.etylcellulose. .ethyl cellulose.
De to granulater blandes i slike vektforhold at prosent-andelene av naproksen som er tilstede i de to granulater i den endelige galeniske formulering, er mellom 30 og 70% av den totale mengde naproksen som er tilstede i selve formuleringen. The two granules are mixed in such a weight ratio that the percentages of naproxen present in the two granules in the final galenic formulation are between 30 and 70% of the total amount of naproxen present in the formulation itself.
Noen eksempler på galeniske formuleringer fremstilt ifølge det som er beskrevet tidligere er angitt nedenfor for illustrering av oppfinnelsen. Some examples of galenic formulations prepared according to what has been described above are given below to illustrate the invention.
EKSEMPEL 1 EXAMPLE 1
Sammensetning av granulatet med regulert frigjøring i mg/ tablett EKSEMPEL 2 Sammensetning av granulatet med regulert frigjøring i Composition of the granules with regulated release in mg/tablet EXAMPLE 2 Composition of the granules with regulated release in
EKSEMPEL 3 EXAMPLE 3
Granulat for oppløsning eller suspensjon inneholdende 500 mg naproksen. Granules for solution or suspension containing 500 mg naproxen.
Sammensetning i mg av granulatet med umiddelbar frigjøring Sammensetning i mg av granulatet med regulert frigjøring Composition in mg of the granules with immediate release Composition in mg of the granules with regulated release
EKSEMPEL 4 EXAMPLE 4
Kapsler inneholdende 375 mg naproksen Sammensetning av granulatet med umiddelbar frigjøring i Capsules containing 375 mg naproxen Composition of the immediate-release granules i
Sammensetning av granulatet med regulert frigjøring i Composition of the granules with regulated release i
EKSEMPEL 5 EXAMPLE 5
Tablett inneholdende 1 gr. naproksen Sammensetning av granulat med umiddelbar frigjøring i Tablet containing 1 gr. naproxen Composition of immediate release granules i
Sammensetning av granulat med kontrollert frigjøring i Composition of granules with controlled release i
Farmakokinetiske forsøk er blitt utført på mennesker for å bevise effektiviteten både umiddelbart og over lang tid for de ovenfor beskrevne galeniske formuleringer. Pharmacokinetic trials have been performed on humans to prove both immediate and long-term efficacy of the above-described galenic formulations.
Disse farmakokinetiske forsøk er blitt utført på grupper som besto av seks friske frivillige, ved undersøkelse av blod-nivåene av naproksen 2, 3, 4, 6, 8, 10, 12, 24 og 36 timer etter administrering av de galeniske formuleringer. These pharmacokinetic experiments have been carried out on groups consisting of six healthy volunteers, by examining the blood levels of naproxen 2, 3, 4, 6, 8, 10, 12, 24 and 36 hours after administration of the galenic formulations.
De verdier som er oppgitt i den følgende Tabell 1 er beregnet på grunnlag av middelverdien av enkeltverdiene for de seks friske frivillige, naproksenet er blitt kontrollert i plasma ved spektrofotometrisk undersøkelse ved 272 nm etter at det har gått gjennom en kolonne for væskekromatografi under høyt trykk (HPLC) ved anvendelse av et apparat av typen LC 601 Perkin-Elmer; verdiene er uttrykt i /ig/ml plasma. The values given in the following Table 1 are calculated on the basis of the mean value of the individual values for the six healthy volunteers, naproxen has been checked in plasma by spectrophotometric examination at 272 nm after it has passed through a high pressure liquid chromatography column ( HPLC) using a LC 601 Perkin-Elmer apparatus; the values are expressed in µg/ml of plasma.
Claims (3)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT03467/86A IT1200178B (en) | 1986-07-23 | 1986-07-23 | GALENIC FORMULATIONS WITH SCHEDULED SALE CONTAINING DRUGS WITH ANTI-FLOGISTIC ACTIVITY |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO873072D0 NO873072D0 (en) | 1987-07-22 |
| NO873072L NO873072L (en) | 1988-01-25 |
| NO174412B true NO174412B (en) | 1994-01-24 |
| NO174412C NO174412C (en) | 1994-05-04 |
Family
ID=11107923
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO873072A NO174412C (en) | 1986-07-23 | 1987-07-22 | Process for preparing a programmed release pharmaceutical formulation for oral use |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4888178A (en) |
| EP (1) | EP0255002B1 (en) |
| JP (1) | JPH0774155B2 (en) |
| AT (1) | ATE75604T1 (en) |
| DE (2) | DE255002T1 (en) |
| DK (1) | DK383987A (en) |
| ES (1) | ES2002089T3 (en) |
| FI (1) | FI92902C (en) |
| GR (1) | GR3004509T3 (en) |
| IE (1) | IE60220B1 (en) |
| IT (1) | IT1200178B (en) |
| NO (1) | NO174412C (en) |
| ZA (1) | ZA874577B (en) |
Families Citing this family (74)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1215726B (en) * | 1988-01-18 | 1990-02-22 | Alfa Wassermann Spa | GALENIC FORMULATIONS WITH SCHEDULED SALE. |
| CH675537A5 (en) * | 1988-03-25 | 1990-10-15 | Ciba Geigy Ag | |
| US5211957A (en) * | 1988-03-25 | 1993-05-18 | Ciba-Geigy Corporation | Solid rapidly disintegrating dosage form |
| DE3822095A1 (en) * | 1988-06-30 | 1990-01-04 | Klinge Co Chem Pharm Fab | NEW MEDICAMENT FORMULATION AND METHOD FOR THE PRODUCTION THEREOF |
| GB8824392D0 (en) | 1988-10-18 | 1988-11-23 | Ciba Geigy Ag | Dispersible formulation |
| US5256699A (en) * | 1988-10-18 | 1993-10-26 | Ciba-Geify Corporation | Dispersible tablet formulation of diclofenac acid free base |
| US4927639A (en) * | 1989-02-02 | 1990-05-22 | Warner-Lambert Company | Modified release gemfibrozil composition |
| US4948581A (en) * | 1989-02-17 | 1990-08-14 | Dojin Iyaku-Kako Co., Ltd. | Long acting diclofenac sodium preparation |
| EP0497977B1 (en) * | 1989-10-26 | 1995-03-15 | Nippon Shinyaku Company, Limited | Gastric preparation |
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|---|---|---|---|---|
| US2793979A (en) * | 1953-03-30 | 1957-05-28 | Smith Kline French Lab | Method of making a sustained release pharmaceutical tablet and product of the method |
| FR1159165A (en) * | 1953-11-03 | 1958-06-24 | Smith Kline French Lab | Pharmaceutical tablet or pill and its manufacturing process |
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| JPS604120A (en) * | 1983-06-22 | 1985-01-10 | Shionogi & Co Ltd | Pharmaceutical preparation of pinacidil of long acting type |
-
1986
- 1986-07-23 IT IT03467/86A patent/IT1200178B/en active
-
1987
- 1987-06-24 ZA ZA874577A patent/ZA874577B/en unknown
- 1987-07-17 AT AT87110389T patent/ATE75604T1/en not_active IP Right Cessation
- 1987-07-17 ES ES198787110389T patent/ES2002089T3/en not_active Expired - Lifetime
- 1987-07-17 DE DE198787110389T patent/DE255002T1/en active Pending
- 1987-07-17 EP EP87110389A patent/EP0255002B1/en not_active Expired - Lifetime
- 1987-07-17 DE DE8787110389T patent/DE3778781D1/en not_active Expired - Fee Related
- 1987-07-22 JP JP62183235A patent/JPH0774155B2/en not_active Expired - Lifetime
- 1987-07-22 NO NO873072A patent/NO174412C/en unknown
- 1987-07-22 DK DK383987A patent/DK383987A/en not_active Application Discontinuation
- 1987-07-22 FI FI873225A patent/FI92902C/en not_active IP Right Cessation
- 1987-07-22 IE IE198187A patent/IE60220B1/en not_active IP Right Cessation
-
1989
- 1989-04-12 US US07/336,507 patent/US4888178A/en not_active Expired - Fee Related
-
1992
- 1992-05-07 GR GR920400501T patent/GR3004509T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI873225A0 (en) | 1987-07-22 |
| ES2002089A4 (en) | 1988-07-16 |
| DK383987D0 (en) | 1987-07-22 |
| NO873072D0 (en) | 1987-07-22 |
| FI92902C (en) | 1995-01-25 |
| DE3778781D1 (en) | 1992-06-11 |
| IE60220B1 (en) | 1994-06-15 |
| EP0255002A1 (en) | 1988-02-03 |
| ATE75604T1 (en) | 1992-05-15 |
| NO174412C (en) | 1994-05-04 |
| DK383987A (en) | 1988-01-24 |
| FI873225A (en) | 1988-01-24 |
| IT1200178B (en) | 1989-01-05 |
| IT8603467A0 (en) | 1986-07-23 |
| FI92902B (en) | 1994-10-14 |
| JPS6354316A (en) | 1988-03-08 |
| ZA874577B (en) | 1988-01-19 |
| ES2002089T3 (en) | 1993-11-16 |
| DE255002T1 (en) | 1988-08-11 |
| JPH0774155B2 (en) | 1995-08-09 |
| US4888178A (en) | 1989-12-19 |
| NO873072L (en) | 1988-01-25 |
| GR3004509T3 (en) | 1993-04-28 |
| IE871981L (en) | 1988-01-23 |
| EP0255002B1 (en) | 1992-05-06 |
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